Canine Osteosarcoma

Class of 2003 (Kramer),
Department of Pathology (Bain, Latimer), Athens Veterinary Diagnostic Laboratory
(Rakich), Department of Anatomy and Radiology (Roberts), and Oncology Service,
Department of Small Animal Medicine (Northrup), College of Veterinary Medicine,
The University of Georgia, Athens, GA 30602-7388

Introduction

Osteosarcoma (OSA) is a
rapidly growing, destructive neoplasm of bone that accounts for 80% of all malignant
bone tumors in dogs.9,10 Neoplasms of the skeleton are more common
in dogs than in any other species. Primary bone tumors such as OSA are five
times more common than metastatic skeletal neoplasms, and malignant tumors are
more common than benign neoplasms.12

Breed, Age,
and Sex Predisposition

Osteosarcoma is most common
in giant and large breed dogs (90%) and is uncommon in small and medium breeds.13 Breeds especially predisposed to development of OSA include Saint Bernards,
Rottweilers, Great Danes, Golden Retrievers, Irish setters, Doberman Pinschers,
and Labrador retrievers. The mean age of occurrence is 7-1/2 years and incidence
of OSA is slightly more common in males than females (1.2:1).10,13

Factors Influencing
Tumor Development

Ionizing radiation, chemical
carcinogens, foreign bodies (including metal implants, such as internal fixators,
bullets, and bone transplants), and pre-existing skeletal abnormalities such
as sites of healed fractures contribute to the development of OSA. In addition,
there have been correlations with genetic predisposition to tumor development
in certain family lines. Dogs with OSA have been found to have aberrations of
the p53 tumor suppressor gene.11 In laboratory animals, both DNA
viruses (polyomavirus and SV-40 virus) and RNA viruses (type C retroviruses)
have been found to induce OSA.13

Sites of
Origin and Metastasis

OSA can be found in both
the appendicular and axial skeleton with the former being 3-4 times more common.10 This neoplasm originates most commonly in the metaphyses of the long bones of
forelimbs, especially the distal radius and proximal humerus. These areas are
especially active during skeletal development and predominate in weight bearing.
OSA also can be found in the distal ulna, proximal and distal tibia, and femur.
OSA usually arises in the medullary cavity, penetrates the cortex, and extends
into the subperiosteum, causing the formation of a large soft tissue mass contiguous
to the bone. Axial skeletal OSA is less common and can involve the ribs, vertebrae,
and skull. Most neoplasms of the skull arise in the cranial vault, zygomatic
arch, and jaw, but occasionally may originate within the nasal cavity. OSA originating
in the skull is usually of the multilobular type and is observed more commonly
in middle-aged dogs. Axial OSA is more common in females.9 Extraskeletal
OSA is rare but may originate in the spleen, adrenal gland, eye, testicle, vagina,
kidney, intestine, mesentery, liver, skin, and mammary gland.

OSA metastasizes primarily
via hematogenous routes and rarely through lymphatics. The lung is the most
common site for visceral metastases. Other metastatic sites include liver, kidneys,
amputation stump, and, rarely, adjacent bones.

Clinical
Signs

The most common clinical
signs of OSA involving the appendicular skeleton are lameness, swelling, and
pain. The considerable soft tissue swelling is predominantly due to edema and
reactive fibroplasia caused by impaired circulation in the subcutaneous and
intramuscular tissue proximal and distal to the tumor.

Congestion, edema, fibroplasia,
and periosteal new bone formation accompany continued tumor expansion. Muscle
atrophy of the affected limb may occur from disuse. Pathological fractures may
occur later in the disease as the neoplasm weakens the cortical bone. Osteolytic
neoplasms are larger, more aggressive, exhibit rapid growth, and cause pathological
fractures. Neoplasms involving the skull and nasal cavity can result in neurological
deficits, dyspnea, nasal obstruction, and a bloody to purulent nasal discharge.

Lymphadenopathy occasionally
can be observed in sites distal to the tumor. Pulmonary metastases may be associated
with the development of hypertrophic osteopathy where space occupying lesions
of the lung incite subperiosteal formation of new bone. Lymph nodes draining
the neoplastic site may become enlarged and firm following tumor mestastasis.

Radiographic
Findings

Radiographically, primary
bone neoplasms have a lytic, productive, or mixed appearance. Characteristic
radiographic findings in OSA include the sunburst pattern, Codmans triangle,
irregular osteolysis that does not cross joint spaces, and variable degrees
of periosteal new bone formation.

The sunburst appearance
is the result of tumor extension, mineralization, and formation of periosteal
spicules in the surrounding tissue (Figs. 1 and 2). OSA is poorly delimited
radiographically because there is a wide zone of transition between abnormal
and normal bone that lacks a sclerotic border at the margin of the lesion. Normal
metaphyseal architecture is lost and the cortical shadow is partially or completely
effaced.

Figure
1. Osteosarcoma of the distal radius in a dog. The extent of the neoplasm
is delineated by the arrows (dorsoventral radiograph).

Figure
2. Osteosarcoma of the distal radius in a dog. Codmans triangle
is formed by the elevation of the periosteal reaction (arrows, lateral radiograph).

Codmans triangle is
the regular periosteal elevation on either side of the lesion that appears irregular
and discontinuous (Fig. 2). Spicular or amorphous patterns of mineralized matrix
may fill the breach in the periosteal response. The adjacent soft tissue swelling
may show neoplastic invasion.

There is little correlation
between the type of radiographic pattern and the biological age of the neoplasm
or its degree of malignancy. Nuclear scintigraphy overestimates tumor margins
but may provide a larger margin of safety when determining the site of proximal
osteotomy during limb-salvage techniques.4

The radiographic differential
diagnosis for proliferative and lytic bone lesions may include bony
proliferation secondary to healing fractures as well as fungal and bacterial
osteomyelitis.

Biochemical
Findings

Alkaline phosphatase activity
may be within the reference interval or increased.2,3 Decreased total
iron binding capacity and increased ferritin concentration may be observed.3 Serum concentrations of zinc, chromium, and iron also may be decreased. Dogs
with OSA have decreased rates of protein synthesis, increased urinary nitrogen
loss, and increased postoperative glucose flux.7 Concentration of
prostaglandin E2 may be increased in dogs with OSA.8 Resting energy
expenditure also has been found to be higher in dogs with OSA.8

Cytology

Fine-needle aspirates of
OSA contain mesenchymal cells that appear round, plump, or fusiform (Fig. 3).
These cells are scattered singly or in small clusters. Individual neoplastic
cells may display anisocytosis, anisokaryosis, karyomegaly, eccentrically located
nuclei, large nucleoli, and basophilic, vacuolated cytoplasm with fine pink
granules (Fig. 3). More well differentiated osteoblasts may have a plasmacytoid
appearance (Fig. 4).

Figure
4. Neoplastic cells exhibit anisocytosis and anisokaryosis. A few cells
have a plasmacytoid appearance. A mitotic figure is present at the upper
left of the image (dog, osteosarcoma, Wright-Leishman stain).

Osteoclasts are large cells
that are multinucleate (Fig. 5). Scattered mitoses also may be observed. Islands
of osteoid may be observed within some clusters of neoplastic cells or within
the background of the smear. Osteoid is amorphous to fibrillar and bright pink
in Wrights-stained cytology specimens (Fig. 6).

Biopsy is often necessary
for the definitive diagnosis of OSA (Fig. 7). The biopsy can be obtained with
a Jamshidi needle that removes a core of the osseous neoplasm. A core biopsy
taken from the center of the lesion is preferred for preoperative diagnostic
purposes. However, initial biopsies often reveal reactive bone and inflammation.
Therefore, multiple core samples may be necessary for a definitive diagnosis.
Most OSAs exhibit three common properties: 1) destruction of normal bony architecture,
2) stimulation of reactive bone production by endosteum and periosteum, and
3) deposition of osteoid. OSA may have a heterogeneous appearance histologically
and have been classified as poorly differentiated, fibroblastic, osteoblastic,
telangectatic, giant cell, or chondroblastic based upon the character of the
neoplastic cell population and the type(s) of matrix produced.12 OSA
also may have a combined or mixed appearance (e.g., a mixture of chondroid
and osteoid matrix), but newer classification schems place these neoplasms within
the osteoblastic subtype.

Figure 7. Poorly
differentiated osteosarcoma with a homogeneous population of spindle cells,
scattered mitoses, and a few pink deposits of osteoid (dog, osteosarcoma,
hematoxylin and eosin stain).

Poorly differentiated and
fibroblastic OSAs have a pleomorphic to fusiform cell population with minimal
deposition of osteoid or production of bony spicules. Poorly differentiated
OSA is a highly aggressive neoplasm. Fibroblastic OSA begins as a lytic tumor.
Approximately 50% of these neoplasms transition onto a combined type as the
neoplastic spindle cells begin to form matrix material. The fibroblastic type
of OSA has the most favorable prognosis.

Osteoblastic OSA is characterized
by anaplastic osteoblasts admixed with plump to spindle shaped osteogenic precursor
cells. Evidence of osteoid deposition or formation of bony spicules is usually
evident; however, these neoplasms occasionally may be lytic or non-productive.

Telangectatic OSA is a rare
neoplasm characterized by variably sized blood-filled spaces that are lined
by tumor cells rather than endothelial cells; mitoses are frequently observed.
This form of OSA is lytic, destructive, and rapidly fatal. Telangectatic OSA
exhibits rapid growth, widespread metastasis, and may be difficult to differentiate
from hemangiosarcoma.

Giant cell OSA appear as
expansive and lytic bone lesions. Histologically, they resemble non-productive
osteoblastic OSA except that the neoplasm may contain large areas in which tumor
giant cells predominate.

The combined or mixed type
of OSA has no dominant matrix pattern. Tumor matrix usually consists of osteoid
in combination with chondroid matrix and/or collagen fibers. This form of OSA
is more common in dogs than any of the other subtypes.10 Chondroblastic
OSA is characterized by a mesenchymal cell population that produces both osteoid
and chondroid matrix.

Treatment

Treatment of OSA can include
surgery, chemotherapy, and radiation therapy. Survival without treatment is
~ 2-6 months.10 Amputation is palliative but rarely increases survival
time. Chemotherapy administered after amputation helps to control metastatic
disease and may increase survival time significantly. The most successful chemotherapy
protocol is a combination of cisplatin and doxorubicin that is administered
following amputation.

Prognosis

The clinical prognosis
for OSA is variable. A poor prognosis is associated with high serum alkaline
phosphatase activity, tumor extension into soft tissue, tumor origin in a hindlimb,
and the presence of pulmonary metastases. The best prognosis is associated with
the fibroblastic subtype of OSA that has the lowest grade of malignancy.
Dogs between
7 and 10 years of age have greater survival times than younger and older dogs.9